The present invention relates to optically active esters of 7-substituted 3,5-difunctionalized 6-heptenoic acids including esters of .beta.,.delta.-diketocarboxylic acids and reduced products thereof. The esters are useful as intermediates for preparing therapeutical agents which inhibit HMG-CoA reductase and are potent for hypercholesterolemia.
For example, optically active esters of .beta.,.delta.-syn-dihydroxycarboxylic acids according to the present invention represented by the following formula (IV): ##STR2## wherein R is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group or a substituted vinyl group; and
Ar is a condensed aromatic group, or optically active enantio-esters of .beta.,.delta.-syn-dihydroxycarboxylic acids represented by the following formula (V'): ##STR3## wherein R and Ar are the same as above, can be converted into 7-substituted (3R, 5S, 6E)-3,5-dihydroxy-6-hepten-5-olides having an inhibitory activity of HMG-CoA reductase or their enantiomers by hydrolyzing the compounds (IV) or (V'), or their enantiomers, followed by lactonizing the resulting acids. PA1 (1) protecting (2S, 4R)-4-hydroxy-6-methoxy-tetrahydropyran-2-carbaldehyde, followed by subjecting the protected compound to the Wittig reaction, hydrolysis and oxidation, successively [J. Med. Chem., 33, 52 (1990)]; or PA1 (2) obtaining a lower alkyl ester or aryl ester of 7-substituted (3R, 5S, 6E)-3,5-dihydroxy-6-heptenoic acid, followed by hydrolyzing the ester [for example, EP 319,847; EP 324,347; J. Med. Chem., 32, 2038 (1989)]. PA1 Ar is a condensed aromatic group; PA1 X.sup.1 and y.sup.1 are not the same and each is a hydrogen atom or a hydroxyl group, or may be combined to represent an oxygen atom which forms a carbonyl group together with the carbon atom to which X.sup.1 and y.sup.1 are attached; and X.sup.2 and y.sup.2 are not the same and each is a hydrogen atom or a hydroxyl group, or may be combined to represent an oxygen atom which forms a carbonyl group together with the carbon atom to which X.sup.2 and y.sup.2 are attached, or an enantiomer thereof. PA1 Ar is a condensed aromatic group, or an enantiomer thereof; PA1 (ii) an optically active ester of .beta.-hydroxy-.delta.-ketocarboxylic acid represented by the following formula (III): ##STR6## wherein R is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group or a substituted vinyl group; and PA1 Ar is a condensed aromatic group, or an enantiomer thereof; PA1 (iii) an optically active ester of .beta.,.delta.-syn-dihydroxycarboxylic acid represented by the following formula (IV): ##STR7## wherein R is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group or a substituted vinyl group; and PA1 Ar is a condensed aromatic group, or an enantiomer thereof; PA1 (iv) an optically active enantio-ester of .beta.,.delta.-syn-dihydroxycarboxylic acid represented by the following formula (V): ##STR8## wherein R is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group or a substituted vinyl group; PA1 Ar is a condensed aromatic group, or an enantiomer thereof. PA1 each of R.sup.1 and R.sup.2 is a straight or branched alkyl group of 1 to 4 carbon atoms.
Furthermore, optically active esters of .beta.,.delta.-syn-dihydroxycarboxylic acids of the formula (IV) or (V'), or their enantiomers can also be utilized for preparing an insect pheromone, endo-1,3-dimethyl-2,9-dioxabicyclo[3.3.1]nonane as described in Tetrahedron Lett., 28, 4773 (1987); ibid., 21, 3013 (1980); J. Org. Chem., 54, 2238 (1989); Chem. Pharm. Bull., 37, 1078 (1989); and Helv. Chim. Acta., 72, 1284 (1989).
Optically active 7-substituted (3R, 5S, 6E)-3,5-dihydroxy-6-hepten-1,5-olides having an inhibitory activity of HMG-CoA reductase have been prepared via either of the following processes:
In the above process (1), the source of the optical activity is sugar derivatives [Tetrahedron Lett., 31, 1869 (1990); ibid., 30, 6015 (1989); ibid., 26, 4995, 2947 (1985)], glutamic acid [J. Chem. Soc., Chem. Commun., 1988, 1417], or ascorbic acid [Tetrahedron Lett., 26, 2951 (1985)], of which functional groups are suitably transformed so that desired precursors are attained. Although the sources are easily available natural products and thus inexpensive, multi-step operations are required for removing unnecessary functional groups and transforming the carbon skeletons in order to obtain the desired precursors. Therefore, the process is less attractive.
The precursor of the above process (2) is often prepared as a racemic mixture. Therefore, the process requires optical resolution for obtaining the desired [3R, 5S] enantiomer with the expense of the other [3S, 5R] enantiomer [J. Med. Chem., 29, 159 (1986)]. Asymmetric synthesis of the [3R, 5S] enantiomer is achieved by repeating asymmetric aldol condensation of a chiral acetic acid ester with an aldehyde twice [Tetrahedron Lett., 28, 1385 (1987) ], by converting a chiral .beta.-hydroxyester into a chiral .delta.-hydroxy- .beta.-ketoester, followed by stereoselective syn-reduction [Tetrahedron Lett., 31, 2545 (1990); ibid., 30, 5115 (1989); Japanese Patent Application Laying Open (KOKAI) Nos. 199945/89, 213270/89; U.S. Pat. No. 4,855,481], or by asymmetric epoxydation of an allylic alcohol [Tetrahedron Lett., 28, 703, 291 (1987)]. These methods, however, require inevitable multi-step operations for transforming the carbon skeletons and controlling the stereochemistry.
The optically active esters of .beta.,.delta.-syn-dihydroxycarboxylic acid are important as precursors for preparing 7-substituted (3R, 5S, 6E)-3,5-dihydroxy-6-hepten-1,5-olides and endo-1,3-dimethyl-2,9-dioxabicyclo[3.3.1]nonane as described above. A short-step synthesis of racemic lower alkyl esters of .beta.,.delta.-syn-dihydroxycarboxylic acid has been reported which comprises a stereoselective syn-reduction of the corresponding lower alkyl esters of .beta.,.delta.-diketocarboxylic acid [Japanese Patent Application Laying Open (KOKAI) No. 165547/89]. However, the method is not applicable to asymmetric synthesis of the esters of .beta.,.delta.-syn-dihydroxycarboxylic acid [Tetrahedron Lett., 29, 6467 (1988)]. This is due to the planar structure of the molecules of the .beta.,.delta.-diketocarboxylic acid esters and to the absence of the known reducing agent or catalyst which may distinguish the Re face and the Si face of the two carbonyl groups. Accordingly, lower alkyl esters of 7-substituted .beta.,.delta.-diketo-6-heptenoic acid are not attractive as precursors of desired 7-substituted (3R, 5S, 6E)-3,5-dihydroxy-6-hepten-5olides and their enantiomers.
Thus, these known methods for preparing optically active heptenolides require tedious multi-step operations and/or optical resolutions of racemic compounds with losing undesired enantiomers.
As a result of the extensive studies, the present inventors have found that an ester of a .beta.,.delta.-diketocarboxylic acid or a .beta.-hydroxy-.delta.-ketocarboxylic acid with a 2-exo-aryl-3-exo-hydroxybornane is useful as a precursor of the optically active ester of .beta.,.delta.-syn-dihydroxycarboxylic acid of the formula (IV) or (V') and that the latter compound is easily converted into the finally desired lactone. The both enantiomers of 2-exo-aryl-3-exo-hydroxybornane are easily obtainable from (+)- or (-)-camphor.